There is a strong correlation between chronic drug use and increase susceptibility to opportunistic infection and opioid addicts are prone to both bacterial and viral infections including HIV. Macrophages form the first line of defense against any invading pathogens, therefore any detriment to the efficient functioning of these cells will severely impair host defense and render the individual more susceptible to infection. Both, chronic morphine use and morphine withdrawal has been shown to inhibit macrophage phagocytosis and decrease microbicidal function. However, the cellular and molecular mechanism by which these functions are modulated has not been delineated. Interestingly, both chronic morphine treatment and morphine withdrawal also results in superactivation of adenylate cyclase. The major focus of this proposal is to determine the mechanisms by which chronic morphine and morphine withdrawal modulate these essential macrophage functions and if elevation of cAMP playa role in these deficits. The central hypothesis of this proposal is that chronic morphine treatment and morphine withdrawal inhibits macrophage phagocytosis and bactericidal killing by modulating signal transduction processes that initiate phagocytosis and subsequent phagolysosomal formation. We further hypothesize that the elevation of cyclic AMP observed foliowing morphine treatment and morphine withdrawal is involved in these functions. Experiments designed in Specific Aim 1: Will investigate the celiular and molecular mechanism by which chronic morphine and morphine withdrawal modulate macrophage phagocytosis: Experiments are designed to initially investigate the dose response, receptor specificity and time course of chronic morphine/morphine withdrawal effects on macrophage Fcgamma mediated phagocytosis and the role of cAMP in these deficits. Subsequent experiments will dissect systematically the cellular and molecular mechanism responsible for modulating phagocytic function. Specific Aim 2: Will investigate the cellular and molecular mechanism by which chronic morphine and morphine withdrawal modulate bactericidal killing. Experiments are designed to initially investigate the dose response, receptor specificity and time course of chronic morphine/morphine withdrawal effects on macrophage bactericidal function and the role of cAMP in modulating this macrophage bactericidal function. Subsequent experiments will determine in a stepwise manner the cellular and molecular mechanism responsible for the deficits. Our long-term goal is to identify the mechanisms by which drug abuse contributes to immunosuppression and susceptibility to infection and to develop therapeutic strategies aimed at modulating these functions.